Clusterin Expression and Localization in the Brain

After its identification in bovine neural tissue1 clusterin was identified in the CNS as a mRNA species with increased abundance in AD hippocampus7,8 and scrapie-infected hamster brain.9 Clusterin mRNA has a similar regional distribution in normal rat and human brain, being widely found in astrocytes throughout the brain, with regional selectivity for neurons.10 Immunohistological localization of clusterin reveals similar selectivity for neurons but few clusterin-positive astrocytes in normal embryonic and postnatal rodent brains.11,12 Three different clusterin immunostaining patterns exist: diffuse, cytoplasmic punctate, and granules without visible cell membranes.11 Unlike apoE, clusterin (apoJ) does not appear to be made by microglia.13 In vitro studies using primary neurons or astrocytes indicate that astrocytes, but not neurons, secrete clusterin.10,13 Clusterin expression (mRNA and immunoreactivity) in normal adult rat brain is highest in ventricular ependyma and choroid plexus epithelial cells.10,14 Also, clusterin has been identified as a component of the cerebrospinal fluid (CSF).15

Clusterin mRNA and protein levels increase in a variety of human neurologic disorders, including Alzheimer's disease (AD),7-9,16,17 multiple sclerosis,18 acquired immune deficiency syndrome (AIDS),18 Pick's disease,9 epilepsy19 and gliomas19 (see chapter 7 for complete review). Clusterin expression is also increased in a variety of experimentally-induced brain injury rodent models representing ischemia,20,21 synaptic repair,22,23 epilepsy,8,24,25 or hormonal alterations26,27 (see chapter 3 for complete review). Human CSF clusterin is increased in patients with evidence for de-myelination, but at normal levels in patients with neurodegenerative and meningeal disease.28,29

Although both neurons and astrocytes contain clusterin mRNA, the increase of clusterin mRNA in the acute-lesioned rodent brain appears to occur primarily within reactive astrocytes.14,21,24 Depending on the lesion paradigm, increased clusterin mRNA is detected in reactive astrocytes within 12 to 48 hours postlesion. Experimentally, astrocytic clusterin mRNA levels can also be manipulated by hormones (corticosterone26; testosterone27) or cytokines (transforming growth factor-p113,30). This increase in astrocytic clusterin mRNA is followed by an increase in clusterin immunoreactivity.22,24,27 Immunohistochemically, clusterin is detected as both cytoplasmic and extracytoplasmic punctate deposits.24 Since cultured astrocytes secrete clusterin,10,13 the increased astrocytic clusterin expression observed after acute trauma may be a source of extracellular clusterin. Increased clusterin immunoreactivity is also associated with neurons after brain lesions in rodents 8,24,25 and humans.17,28,31-33 Additionally, clusterin is found in association with dystrophic neurites and p-amyloid (Ap) in plaques of AD.28,31,32,34

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